PMID- 17925795 OWN - NLM STAT- MEDLINE DCOM- 20090408 LR - 20150813 IS - 1476-5578 (Electronic) IS - 1359-4184 (Linking) VI - 14 IP - 1 DP - 2009 Jan TI - The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. PG - 51-9 AB - Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium- or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium- or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3alpha or GSK-3beta isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers. FAU - Yasuda, S AU - Yasuda S AD - Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA. FAU - Liang, M-H AU - Liang MH FAU - Marinova, Z AU - Marinova Z FAU - Yahyavi, A AU - Yahyavi A FAU - Chuang, D-M AU - Chuang DM LA - eng GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20071009 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Antimanic Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 614OI1Z5WI (Valproic Acid) RN - 660YQ98I10 (Potassium Chloride) RN - G4962QA067 (Lithium Chloride) SB - IM MH - Animals MH - Antimanic Agents/*pharmacology MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Cells, Cultured MH - Cerebral Cortex/cytology MH - Dose-Response Relationship, Drug MH - Embryo, Mammalian MH - Enzyme Inhibitors/pharmacology MH - Enzyme-Linked Immunosorbent Assay MH - Lithium Chloride/*pharmacology MH - Membrane Potentials/drug effects MH - Neurons/*drug effects MH - Patch-Clamp Techniques MH - Potassium Chloride/pharmacology MH - Promoter Regions, Genetic/*drug effects MH - RNA, Messenger/metabolism MH - RNA, Small Interfering/pharmacology MH - Rats MH - Time Factors MH - Transfection MH - Valproic Acid/*pharmacology EDAT- 2007/10/11 09:00 MHDA- 2009/04/09 09:00 CRDT- 2007/10/11 09:00 PHST- 2007/10/11 09:00 [pubmed] PHST- 2009/04/09 09:00 [medline] PHST- 2007/10/11 09:00 [entrez] AID - 4002099 [pii] AID - 10.1038/sj.mp.4002099 [doi] PST - ppublish SO - Mol Psychiatry. 2009 Jan;14(1):51-9. doi: 10.1038/sj.mp.4002099. Epub 2007 Oct 9.